Nuclear receptors constitute a large superfamily of transcription factors with 48 members in humans. The subfamily of steroid receptors (SR) is represented by the receptors for estrogens (estrogen receptor (ER)-α and ER-β), androgen receptors (AR), glucocorticoid receptors (GR), progesterone receptors (PR), and mineralocorticoid receptors (MR). Steroid receptors are prototypical ligand-dependent transcription factors and binding of cognate steroid is an absolute requirement for transcriptional activation. The simple one ligand-one receptor model does not apply to the sex steroid receptors which can receive multiple inputs and interact with one another to confer a downstream response. We hypothesize that there is an interaction between the sex steroid receptors in the placenta that mediates the adaptation of the fetus to a stress in pregnancy in a sex specific manner.
Our research has identified multiple SR isoforms in the human placenta with 12 GR isoforms, 7 AR isoforms and multiple immunoreactive proteins associated with the receptor antibodies for PR and ER including PR A, B and C and ERα and β. Our aim is to model the interaction between the steroid receptor proteins and define their impact on downstream signaling pathways associated with inflammation and fetal growth. To date we have identified that in the presence of maternal asthma, placental GRβ is upregulated protecting the male fetus from the anti-proliferative effects of glucocorticoids. However, in order for the male fetus to continue to grow in the presence of maternal asthma there was a rise in the placental AR expression which was correlated with increased expression of IGF-1, IGP BP5 and IGF-1R. These initial investigations suggest that the interaction between the placental steroid receptors are an essential mechanism for the growth and survival of the fetus.